The long-term objective of our proposed program is to develop a non-invasive chronic wound treatment that combines optic and acoustic modalities in a synergistic way. This theragnostic, i.e. thera(peutic) and (dia)gnostic technology, merging a non-invasive ultrasound therapy with Near Infrared (NIR) diagnostic monitoring, will allow a wound care provider to prescribe low frequency ultrasound therapy through a Band-Aid(R)-like wearable patch, assess the status of wound healing with digital imaging and NIR, and adjust the ultrasound parameters as necessary. The treatment considered here involves exposure of the wound to non-invasive low (20-100 kHz) frequency ultrasound energy with periodic real-time digital and near infrared (NIR) monitoring of tissue optical properties related to wound healing parameters. Thus, in vivo acquired diagnostic information provided by an optic sensor will be combined with therapy and used to direct and optimize wound healing treatment. Our ultimate goal is to develop a sterile, patient friendly patch containing an ultrasound applicator and associated electronic controls that could be directly applied by a patient to the wound. This wearable patch will allow for frequent (daily or even multiple exposures per day) application of the ultrasound therapy without a return of the patient to the clinic and will significantly increase patient compliance with the therapy. In order to accomplish this goal, we will establish the optimal ultrasound exposure parameters that will serve as the basis for the prototype Band-Aid(R)-like wearable ultrasound applicator. The novelty of our approach consists of using non-invasive, safe levels of low frequency ultrasound therapy with non-invasive optical diagnosis of wound healing enabled through the unique development of a low-cost wearable ultrasound applicator. This systematic approach will be validated through a study of venous ulcers in humans, providing quantitative information not available currently. Our underlying hypothesis is that low frequency ultrasound can provide an effective therapy for chronic wounds and that application of this therapy can be optimized by assessment of wound healing through NIR monitoring. Accordingly, our specific aims are: Specific Aim 1: Develop optimal exposure matrix protocol for ultrasonically assisted chronic wound healing. Identify optimal ultrasound low frequency (20 or 100kHz) and assess effect of total energy density on wound healing. Wound healing is assessed by NIR and wound size determination. Specific Aim 2: Based on the outcomes of Specific Aim 1, develop and test an early prototype of the Band-Aid(R)-like wearable ultrasound patch device based chronic wound ultrasound applicator. Specific Aim 3: Using the prototype of the ultrasound applicator developed in Specific Aim 2 identify the possible role of (inertial and stable) cavitation and mechanical stresses as possible mechanisms, and rule out thermal effects. Specific Aim 4: Validate the Band-Aid(R)-like wearable ultrasound patch prototype in human patients under the optimal conditions identified in Specific Aim 1. At the completion of this research, the optimum exposure matrix will be established and an early prototype of the wearable chronic wound applicator will be constructed and tested. The results of this project will also provide insights into the possible mechanisms affecting wound healing.